Application Note: Common cold chain 483s & suggested solutions

7/30/2019 Application Note: Common cold chain 483s & suggested solutions

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FDA & ICH: Regulations and Standards orTemperature-Controlled Supply Chains

The two greatest risks in pharmaceutical and biotechnology supply chains are the

risk o product becoming adulterated during transport and the risk o non-compliancewith ederal regulations, guidelines and standards. Ater that the greatest concern

o manuacturers and distributors is cost containment in an increasingly globalized,

increasingly complex supply chain.

Two organizations that carry signicant regulatory weight are the combined orceso the US Food and Drug Administration (FDA) and International Conerence on

Harmonisation o Technical Requirements or Registration o Pharmaceuticals orHuman Use (ICH).The FDA co-ounded the ICH with the European Community in

1990 with the goal o creating a globally harmonized approach to the understanding

and application o technical guidelines or drug manuacturers. The outcome oharmonisation was to decrease unnecessary replication o costly regulatory processes,

thereby promoting more ecient manuacturing, processing and distribution methodsor regulated products on a global scale.

Whereas the jurisdiction o the FDA is primarily in the United States and Puerto Rico, theICH is an international entity that involves the US, Japan and the European Union. Other

parties involved in ICH include:

The Pharmaceutical Research and Manuacturers o America (PhRMA) The Center or Drug Evaluation and Research (CDER)

The Center or Biologics Evaluation and Research (CBER)

The European Commission

The European Federation o Pharmaceutical Industries Association

The Japanese Ministry o Health, Labor and Welare

The Japanese Pharmaceutical Manuacturers Association

ICH Secretariat1

The International Federation o Pharmaceutical Manuacturers & Associations (IFPMA)

And other ICH sponsors: Health Canada, the European Free Trade Area (EFTA), and

the World Health Organization2

In this application note we look at the

FDA regulations and ICH guidelines thataddress supply chain management or

temperature-controlled pharmaceuticaland biotechnical products, including:

ICH Guidance or Industry Q1A(R2)

Stability Testing o New DrugSubstances and Products

ICH Harmonised Tripartite Guidelines

Q6A and Q6B(Test Procedures andAcceptance Criteria or New Drugs and

New Biotechnology

FDA CFR Title 21 203.32, 203.36, 211.150

FDA 483 observations on cold chainapplications with suggested deviation

osets

Moving temperature-sensitive products

necessarily renders the supply chain acold chain (sometimes also called cool

chain) and products that all under thepurview o ederal law and enorcement

agencies urther evolves the logistics

process into a regulatedcold chain.

However, there is currently no singlestandard, guidance, regulator, document

or arbiter with the nal say on acompliant cold chain or a given region.3

Instead, manuacturers and distributors

ace a myriad o regulations, conerences,technical reports and recommendations

rom disparate agents.

A growing list o documents, legislation,

requirements, recommendations andguidelines reveal how ragmented the

current regulatory environment is in coldchain management:

The EU Guide to Good ManuacturingPractice, Annex 13

The Guidelines on Good DistributionPractice (GDP) o Medicinal Products

CDC Guidelines or Maintaining and

Managing the Vaccine Cold Chain

WHO Guidelines on the internationalpackaging and shipping o vaccines

PDA Technical Report 39

The US Code o Federal Regulations

US and European Pharmacopoeia

/ APPLICATION NOTE

COLD CHAIN COMPLIANCE


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A Scientifc Approach toCold Chain Management

To simpliy your approach to coldchain management into a principle,

ask yoursel what any regulatory

body (and inspector) will want toknow. From a regulatory standpoint,

the question always comes down tothe quality and completeness o your

scientic (that is, veriable) knowledgeo a product and the environments it

moves through beore reaching theend user. A common introduction to

many an FDA Form 483 observation is:

Your frm did not establishscientically sound and appropriatespecifcations, standards, sampling

plans, and test procedures designed

to assure that components, productcontainers, in-process materials,and transport methods conorm toappropriate standards o identity,strength, quality and purity.

As in all FDA-regulated applications,establishing and documenting data

on your operating environments that

are scientically sound should beyour underlying goal in compliance

eorts. Cold Chain Quality engineers,Cold Chain managers, Packaging

engineers and other stakeholders

must understand their environmentalconditions and product parameters

better than any inspector. Aterthe knowledge o conditions and

parameters is established comes thedocumentation o that knowledge,

without which, it may as well not exist.

In the ollowing sections, we reviewsome o the main FDA and ICH

regulations and guidelines concerning

supply chain applications. Wellalso provide some samples o 483

observations and discuss what sort ocorrective and/or preventive actions

could oset the (possible) deviationsin the samples.

ICH Guidance

The ICH publication: Guidance orIndustry: Q1A(R2) Stability Testing o

New Drug Substances and Products4describes proper management o

temperature excursions in shipping

and short-term storage applications.For testing and acceptance criteria

o closure systems or new drugs

(chemical) and new biotechnology,reer to these guidances:

Q5C Quality o Biotechnological

Products: Stability Testing oBiotechnological/Biological

Products5

Q6A Specications: Test Proceduresand Acceptance Criteria or New

Drug Substances and New DrugProducts: Chemical Substances

Q6B Specications: Test Procedures

and Acceptance Criteria or NewDrug Substances and New Drug

Products: Biotechnological/

Biological Products

While not specic to distribution

applications, these guidances contain

valuable criteria or creating tests thatwill ensure products are protected

during shipping and short-termstorage. A crucial element to creating a

compliant cold chain is to create teststhat accurately represent the real-

time, real-world shipping environment,

including primary and secondarycontainers, transport and storage

durations, seasons and climatic zones.

It should be remembered that theICH guidelines arent standards;

rather, they are guidance ormeeting technical requirements

and are intended to be used

in combination with any regionalrequirements 8. Quality managers,

cold chain engineers, and anyonewhose responsibilities include a

temperature-controlled supply chainare accountable or understanding

ICH recommendations. FDA inspectors

oten cite non-adherence to ICH, asseen here in this Warning Letter:9

Please note that a guidancedocument entitled Q7A Good

Manuacturing Practice Guidanceo Active Pharmaceutical

Ingredients (ICH CGMP Guidance),prepared under the auspices othe International Conerenceon Harmonisation o Technical

Requirements or Registration oPharmaceuticals or Human Use(ICH), describes current goodmanuacturing practice (cGMP)

Although the ICH cGMP Guidancedoes not impose requirements, [the]

FDA considers its recommendations,

as well as alternatives intendedto accomplish the same goals and

provide an equivalent level o qualityassurance, in determining whethera frms [products] have been

manuactured, processed, packed,and held according to current goodmanuacturing practice under Section501(a)(2)(B) o the Act.

In the Q5 guideline, under Storage

Conditions Part 6.3, Acceleratedand Stress Conditions10 the ICH

recommends that stress tests be

perormed in order to dene theconditions that may occur during

transportation will aect the product.To recommend testing, the guide is

necessarily broad because o all the

dierent types o products that might

be shipped. The testing will not onlydetermine the conditions that impactthe product, but should also determine

which tests are best or determining

stability.

Studies under stress conditions maybe useul in determining whetheraccidental exposures to conditionsother than those proposed(e.g., during transportation) aredeleterious to the product andalso or evaluating which specifctest parameters may be the bestindicators o product stability.

Studies o the exposure o thedrug substance or drug product toextreme conditions may help toreveal patterns o degradation; i so,such changes should be monitoredunder proposed storage conditions.Conditions should be careullyselected on a case-by-case basis.11

Likewise or new drug substances andproducts:

Data rom the accelerated storage

condition and, i appropriate, romthe intermediate storage conditioncan be used to evaluate the eecto short term excursions outside thelabel storage conditions (such asmight occur during shipping).12


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RECEIVERAIRPORTAIRPORTPRODUCER

Who? Where? How? Duration?

Temperature range? Excursions?

Food & Drug Administration (US)

Three key regulations rom the FDA that address cold chain are:

21 CFR 203.32 Prescription Drug Marketing Drug sample storage and handling requirements.

This subpart (D--Samples) contains two parts that stipulate that (a) Storage and handling conditions not adversely aect the drug

and (b) manuacturers, distributors o record, and their representatives comply with all compendial and labeling requirements.13

21 CFR 203.36 Fulllment houses, shipping and mailing services, comarketing agreements, and third-party recordkeeping looks

at comarketing agreements with any third party involved in shipping and storing drug samples. This section states that the

manuacturer or distributor is responsible or record keeping and documentation and must comply with the Prescription Drug

Marketing Act (PDMA) and amendments. The PDMA document contains recommendations relating to 21 CFR Parts 203 and 205 and

outlines how to document drug products that pass rom manuacturers to Authorized Distributor o Record (ADR) and provisions

regarding pedigrees.14

21 CFR 211.150 o Subpart H: Holding and Distribution - Distribution procedures states that these products must be shipped within:

appropriate temperatures and under appropriate conditions in accordance with requirements, i any, in the labeling o such drugs,

or with requirements in the current edition o an ocial compendium, such as the United States Pharmacopeia/National Formulary

(USP/NF).

(2) Appropriate manual, electromechanical, or electronic temperature and humidity recording equipment, devices, and/or logs

shall be utilized to document proper storage o prescription drugs.

(3) The recordkeeping requirements in paragraph () o this section shall be ollowed or all stored drugs. () Recordkeeping states that drug distributors must maintain records and inventories that show receipt and distribution or

other disposition o prescription drugs. These records must include the source o the drugs, the address o the location that the

drugs were shipped rom, the identity and quantity, and the dates o receipt/distribution/other disposition. Records must be kept

and accessible or inspection or 3 years ater the date o their creation.15

The regulations reveal what one expects: documentation is key to compliance with ederal regulations. Unortunately, the supply chain has

many links; each requires thorough records and many stakeholders can contribute to a document portolio o a given product in the chain.

Stakeholders typically include drug or biotechnical testing laboratories and manuacturers, contract manuacturers and packagers,

distribution centers, wholesalers, and nally, healthcare acilities or pharmacies. The distribution path can include dierent types o

transportation and several climatic zones, and each new mode o transport and location will come with its own temperature fuctuations.

When setting up a cold chain management system that complies with ederal regulations, youll need to create or obtain detailed records

o stability data, geographical data (including climatic zones), shipping and storage durations at each point in the journey, and contingency

procedures or delays, out-o-specication conditions or other unexpected events. In the next section, well look at some common GDP

deviations that can occur along the cold chain.

Typical Cold Chain Distribution


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Form 483 Excerpt Suggested Solution

Standard operating procedures do notdescribe how kits are packaged or labeledto ensure that temperature specicationsare maintained during shipment.

The problem here could be that the SOP lacked the appropriate inormationeven though a package and labelling perormance qualication study wasdone, or the study wasnt done at all. Proper shipping validation would producea document outlining standard packaging and labeling conguration. SOPsensure that kits are packaged in the validated conguration and labeled with theapplicable temperature specication. Primary packaging should be qualied in theIdentication o Requirements process (See: TR3917 process fow) and included ina Functional Requirements document. Include the packaging summary created orthe Functional Requirements in the shipping SOP.

No records are available to ensure thatproducts are shipped and maintainedwithin their storage temperature

requirements.

No record available could mean:

1. They monitored but no records were kept, or the records were lost. I the latter,this is a record storage and retention issue. Or,

2. They dont monitor and had no records.

Whats required is a monitoring program o some sort; however, it must beproceduralized to make sure records are reviewed and maintained.

The standard operating procedure lacksacceptance criteria or the storage andmovement o material between two sites.

This may just be a poor SOP. They might not have had the specications, but thatwould have shown up in the Form 483. More likely is that the SOP was just poorlywritten and/or not well reviewed. Three elements o acceptance criteria are:

1. They dene the ways that SOP users conrm that the transport and holdingprocesses are unctioning as intended.

2. They identiy the objective results o a process; they must take into account theproduct specications, and process fow requirements.

3. Acceptance criteria must be measureable and veriable.18

Temperature specications are notdened or the shipment o packaged,temperature-monitored bulk productsand lled vials to and rom the llingcontractor.

They need to get the specications dened and included in a shipping SOP. A copyo the batch record, stability statement, and/or a Certicate o Analysis (COA)should provide a history o the conditions pertinent to the quality o the nalproduct.19

Contracts should also contain handling instructions or all bulk and nishedproducts.20

Bulk material intended or rerigeratedstorage is let at ambient conditions orseveral days beore shipping.

Whats required is either an SOP, or a way to make sure the existing SOP isollowed. A simple solution may be installing a validated storage environmentbecause one is lacking in the loading/shipping area.

The shipment by truck o nishedvials rom one site to another is not yetvalidated.

A gap in qualiying the entire fow o transportation indicates a lack o identiyingthe transportation process and perorming the necessary qualications outlined inPDA TR39.17

Cold Chain 483sHere are several excerpts rom Form 483s16 that were issued on observations directly related to cold chain management. In the

right side o the table weve suggested solutions or avoiding deviations like those excerpted below and maintaining a GDP-compliant cold chain.

ConclusionThe goal o any supply chain is to transport products rom the manuacturer to the consumer. However, the success o a

supply chain depends on and is measured by its ability to deliver products that can serve their ultimate purpose with the enduser. In pharmaceutical supply chains, this means that a product must arrive unadulterated and with its ecacy ully intact.

In the context o a successul supply chain, organizations that enorce regulations and create quality standards act not only

as arbiters, but as partners in quality. With globalization and emerging markets, many countries look to ICH and the FDA orguidance in approaches to improving supply chain control and perormance. It ollows that basing your regulatory compliance

rmly in the regulations, standards and guidelines o these two organizations will ensure that the undamental requirements oa sae supply chain or drugs and biotechnology are satised.


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For more inormation on cold chainapplications, contact your local Vaisalarepresentative at [email protected].

Re. B211216EN-A Vaisala 2012This material is subject to copyright protection, with all copyrights

retained by Vaisala and its individual partners. All rights reserved.

Any logos and/or product names are trademarks o Vaisala or

its individual partners. The reproduction, transer, distribution or

storage o inormation contained in this brochure in any orm

without the prior written consent o Vaisala is strictly prohibited.

All specifcations technical included are subject to change

without notice.

Sources

1 Oversees documentation

2 From: ICH and FDA: A Valuable Cooperative by Corrine Knight and Annette Dunn, http://www.CodaCorpUSA.com/blog or

http://blog.CodaCorpUSA.com/2010

3 Preserving the Cool Chain, Mary Simpson, Edith Penxten, Elie Dechesne, http://www.pharmaceuticaloutsourcing.com/pd/POD001_054E_Bristol-Myers.pd, retrieved 5/22/2012

4 http://www.da.gov/downloads/RegulatoryInormation/Guidances/ucm128204.pd, retrieved 6/25/2012

5 ICH Harmonised Tripartite Guideline: Quality o Biotechnical Products: Stability Testing o Biotechnical/Biological Products Q5C http://

www.ich.org/fleadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q5C/Step4/Q5C_Guideline.pd , retrieved 5/23/2012

6 The ull name o ICH is the International Conerence on Harmonisation o Technical Requirements or Registration o Pharmaceuticals or

Human Use Source: http://www.ich.org/about/aqs.html, retrieved May 22, 2012

7 Guidance or Industry Q1A(R2) Stability Testing o New Drug Substances and Products http://www.da.gov/downloads/

regulatoryinormation/guidances/ucm128204.pd

8 See ICH Work Products, Are the ICH Guidelines standards? http://www.ich.org/about/aqs.html, retrieved 5/22/2012

9 http://www.da.gov/ICECI/EnorcementActions/WarningLetters/2007/ucm076496.htm

10 Q5 Stability Testing o Biotechnical/Biological products

11 Page 8, Q5 Stability Testing o Biotechnical/Biological products

12Page 9 Stability Testing o New Drug Substances and Products http://www.ich.org/fleadmin/Public_Web_Site/ICH_Products/

Guidelines/Quality/Q1A_R2/Step4/Q1A_R2__Guideline.pd

13 http://www.accessdata.da.gov/scripts/cdrh/cdocs/ccr/CFRSearch.cm?CFRPart=203, retrieved 5/22/2012

14 A drug pedigree is a statement o origin that identifes each prior sale, purchase, or trade o a drug, including the date o those transactions

and the names and addresses o all parties to them. See CPG Sec. 160.900 Prescription Drug Marketing Act Pedigree Requirements under

21 CFR Part 203 http://www.da.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm073857.htm, retrieved

6/14/2012

15 http://www.accessdata.da.gov/scripts/cdrh/cdocs/ccr/CFRSearch.cm?r=205.50, retrieved 5/22/2012

16http://www.da.gov/AboutFDA/CentersOfces/OfceoGlobalRegulatoryOperationsandPolicy/ORA/

ORAElectronicReadingRoom/deault.htm , obtained through the Freedom of Information (FOI) Act at the FDA electronic reading

room, accessed 5/22/2012

17 Parenteral Drug Associations Technical Report No. 39 Revised 2007 Guidance or Temperaure-Controlled Medicinal Products: Maintaining

the Quality o Temperature-Sensitive Medicinal Products through the Transportation Environment covers the methods o qualiying the

cold chain applications.

18 IPEC-Americas Certifcate o Analysis Guide or Bulk Pharmaceutical Excipients (Glossary, Page 17) oers a defnition o acceptance

criteria that can be extrapolated to aid in understanding acceptance criteria use in SOPs or pharmaceutical manuacturing processes;

The specifcations and acceptance/rejection limits, such as acceptable quality level and unacceptable quality level, with an associated

sampling plan that are necessary or making a decision to accept or reject a lot or batch o raw materials, intermediate, packaging material or

excipient. It is important to note that acceptance criteria as defned by the IPEC carries an inherent defnition o rejection criteria that is,

all that is outside o a minimum or maximum limitation.

19Quality assurance o pharmaceuticals A compendium o guidelines and related materials WHO, Page 17 http://apps.who.int/

medicinedocs/documents/s14136e/s14136e.pd , retrieved 5/28/2012

20 See also: Quality assurance o pharmaceuticals WHO, Page 27: Section 7. Contract production and analysis
http://www.codacorpusa.com/bloghttp://blog.codacorpusa.com/2010http://www.pharmaceuticaloutsourcing.com/pdf/POD001_054E_Bristol-Myers.pdfhttp://www.pharmaceuticaloutsourcing.com/pdf/POD001_054E_Bristol-Myers.pdfhttp://www.pharmaceuticaloutsourcing.com/pdf/POD001_054E_Bristol-Myers.pdfhttp://www.pharmaceuticaloutsourcing.com/pdf/POD001_054E_Bristol-Myers.pdfhttp://www.pharmaceuticaloutsourcing.com/pdf/POD001_054E_Bristol-Myers.pdfhttp://www.fda.gov/downloads/regulatoryinformation/guidances/ucm128204.pdfhttp://www.fda.gov/downloads/regulatoryinformation/guidances/ucm128204.pdfhttp://www.fda.gov/downloads/regulatoryinformation/guidances/ucm128204.pdfhttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_R2__Guideline.pdfhttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_R2__Guideline.pdfhttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_R2__Guideline.pdfhttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_R2__Guideline.pdfhttp://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/default.htmhttp://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/default.htmhttp://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/default.htmhttp://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/default.htmhttp://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/default.htmhttp://apps.who.int/medicinedocs/documents/s14136e/s14136e.pdfhttp://apps.who.int/medicinedocs/documents/s14136e/s14136e.pdfhttp://apps.who.int/medicinedocs/documents/s14136e/s14136e.pdfhttp://apps.who.int/medicinedocs/documents/s14136e/s14136e.pdfhttp://apps.who.int/medicinedocs/documents/s14136e/s14136e.pdfhttp://apps.who.int/medicinedocs/documents/s14136e/s14136e.pdfhttp://blog.codacorpusa.com/2010http://www.codacorpusa.com/bloghttp://apps.who.int/medicinedocs/documents/s14136e/s14136e.pdfhttp://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/default.htmhttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_R2__Guideline.pdfhttp://www.fda.gov/downloads/regulatoryinformation/guidances/ucm128204.pdfhttp://www.pharmaceuticaloutsourcing.com/pdf/POD001_054E_Bristol-Myers.pdf

Application Note: Common cold chain 483s & suggested solutions

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